2-hydroxy-4-aryl-quinolines



United States Patent 3,542,785 2-HYDROXY-4-AR -QUINOLINES Richard William James Carney, New Providence, N.J.,

assignor to Ciba Corporation, New York, N.Y., a corporation of Delaware No Drawing. Filed May 15, 1967, Ser. No. 638,594 Int. Cl. C07d 33/46 U.S. Cl. 260-289 1 Claim ABSTRACT OF THE DISCLOSURE 2-amino-4-aryl-quinolines of the formula Am=an amino or hydrazino group,

R =H, aliphatic, araliphatic or aromatic radical,

R =aromatic radical,

R =H, alkyl, alkoxy, alkylmercapto, halogeno, CF

N0 or amino,

acyl derivatives, quaternaries and salts thereof, and corresponding 2-hydroxy compounds exhibit antiinflammatory eifects. The Z-hydroxy compounds which exhibits antiinflammatory effects are those of the formula in which Ph stands for a 1,2-phenylene radical, R for hydrogen, an aliphatic, araliphatic or aromatic radical, R for a carbocyclic or heterocyclic aromatic radical and X for oxygen or sulfur.

SUMMARY OF THE INVENTION The present invention concerns and has for its object the provision of new 2-amino-4-aryl-quinolines, more particularly those of the Formula I 3,542,785 Patented Nov. 24, 1970 p CC for the preparation of these products. Said compositions are useful as antiinflammatory agents, preferably for oral application, in the treatment of tissue inflammations, such as arthritic inflammations and similar conditions.

DESCRIPTION OF THE PREFERRED EMBODIMENTS The 1,2-phenylene radical Ph is unsubstituted or substituted by one or more than one of the same or diiferent substituents attached to any of the positions available for substitution. Such substituents are, for example, lower alkyl, such as methyl, ethyl,nor i-propyl or -butyl, etherified hydroxy or mercapto, for example, lower alkoxy or alkylmercapto, such as methoxy, ethoxy, nor ipropoxy or -butoxy, methylor ethylmercapto, esterified hydroxy, for example, halogeno, such as fluoro, chloro 0r bromo, trifluoromethyl, nitro or amino, for example, di-lower alkylamino, such as dimethylarnino or diethylamino. Preferred 1,2-phenylene radicals Ph are 1,2- phenylene, (lower alkyl)-l,2-phenylene, (lower alkoxy)- 1,2-phenylene, (lower alkylmercapto)-1,2-phenylene, (halogeno -1,2-phenylene. (trifluoromethyl) -1,2-phenylene, (nitro)-1,2-phenylene or (di-lower alkylamino)-1,2- phenylene.

An aliphatic radical R R and/or R represents especially loweralkyl, such as methyl, ethyl, nor ipropyl, -butyl, -pentyl, -hexyl or -heptyl. It may also stand for lower alkenyl, such as allyl or methallyl, cycloalkyl or cyc1oalkyl-lower alkyl having from 3 to 8, especially from 5 to 7, ring-carbon atoms, such as cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl, cyclopropylmethyl, cyclopentylmethyl, 2-cyclopentylethyl, cyclohexylmethyl, l-cyclohexylethyl or cycloheptyhnethyl. An araliphatic radical is preferably monocyclic carbocyclic aryl-lower alkyl, such as benzyl, 1- or 2- phenylethyl. These radicals are unsubstituted or contain additional substituents in the aromatic portion, such as those mentioned for Ph, and/or in the aliphatic portion hydroxy. Such radicals are, for example, hydroxy-lower alkyl, such as Z-hydorxy-ethyl, 2- or 3-hydroxy-propy1, 2-, 3-or 4-hydroxy-butyl.

R and R when taken together, also represents lower alkylene, aralkylene, aza-, oxaor thia-alkylene, N-(lower alkyl, hydroxy-lower alkyl or phenyl)aza-alkylene, in which the hetero atoms are separated from each other by at least 2 carbon atoms, such as 1,2-ethylene, 1,4- butylene, 1,4- or 1,5-pentylene, 3-(methyl or phenyl)- 1,5-pentylene, 2,5- or 1,6-hexylene or 2,6-heptylene; 3- aza-1,5-pentylene, B-(methyl, ethyl, 2-hydroxyethyl or phenyl)-3-aza-1,5-pentylene, 3-(oxa or thia)-1,5-pentylene.

An aromatic radical R and/or R and that present in the above araliphatic radical, particularly stands for monoor bicyclic carbocyclic aryl, i.e., phenyl, 1- or 2- napht'hyl, or monocyclic heterocyclic aryl, such as furyl, thienyl or pyridyl. Said aryl groups are unsubstituted or contain one or more than one of the same or different substituents attached to any position available for substitution, for example those mentioned for Ph. They primarily stand for phenyl, (lower alkyl)-phenyl, (lower alkz0jXy)-pheny1,\ (lower alkylmercapto)-phenyl, (halogeno)-phenyl, (trifluoromethyD-phenyl, (nitro)-phenyl, (di-lower alkylamino)-phenyl, pyridyl, (lower alkyl)- pyridyl, furyl, (lower aIkyD-furyl, thienyl or (lower alkyl -thienyl.

The acyl derivatives of the invention are particularly those of carboxylic acids, preferably of aliphatic, araliphatic or aromatic carboxylic acids, such as those mentioned below, especially of lower alkanoic acids, such as acetic, propionic, butyric or pivalic acid. The quaternaries of the invention are preferably the lower alkyl or aralkyl quaternaries.

The compounds of this invention exhibit valuable pharmacological properties. Apart from diuretic effects, they show primarily antiinfiammatory activity, as can be demonstrated in animal tests using, for example mammals, such as rats or dogs, as test objects. Besides their above-mentioned use, they are also valuable diuretics or intermediates in the preparation of other useful products, particularly of pharmacologically active compounds. Thus the corresponding 2-amino 4 aryl-3,4-dihydroquinolines, disclosed in copending application Ser. No. 638,593, filed May 15, 1967, are obtained from the compounds of this invention by hydrogenation.

Particularly useful are the compounds of Formula I in which Ph stands for 1,2-phenylene, (lower alkyl)-l,2- phenylene, (lower alkoxy) 1,2 phenylene or (halogeno)-1,2-phenylene, R for hydrogen or lower alkyl, R for hydrogen, amino, di-lower alkylamino, lower alkyl, lower alkenyl, cycloalkyl or cycloalkyl-alkyl with 3 to 6 ringand l to 4 chain-carbon atoms or R -lower alkyl, R and R when taken together, also stand for lower alkylene R -lower alkylene, or lower aza-, oxa-, or thiaalkylene or N-lower alkylor hydroxy-lower alkylazaalkylene, wherein the heteroatoms are separated from each other by at least 2 carbon atoms, R for hydrogen, lower alkyl or R and each of R R and R for phenyl, (lower alkyl)-phenyl, (lower alkoxy)-pheny1 or (halogeno)-phenyl, and therapeutically useful acid addition salts thereof.

Especially mentioned are the compounds of Formula II R R11 I Re i N in which R stands for hydrogen methyl or ethyl, R for amino, methyl, ethyl, propyl, allyl, cyclopropyl, cyclopropylmethyl, Z-hydroxy-ethyl, benzyl, 4-fluoro-benzyl or Z-pyridylmethyl, or R and R together for 1,4-butylene, 1,5-pentylene, B-phenyl 1,5 pentylene, 1,6-hexylene, 3-metbyl 3 aza-l,5-pentylene or 3-oxa-l,5-pentylene, R for hydrogen, methyl or phenyl, R for phenyl or 4- methoxy-phenyl and R for hydrogen or chloro, and therapeutically useful acid addition salts thereof which, when given orally to rats at doses between about 5 and 50 mg./kg./day, preferably between about 10 and 2S mg./kg./day, show outstanding antiinflammatory elfects according to the granulama pouch or carrageenin paw test.

The compounds of this invention are prepared according to known methods. For example, the process for their preparation consists in:

(a) Reacting a 2-(hydroxy or mercapto)-aryl-quinoline, more particularly such of the Formula III XH N (III) in which X stands for oxygen or sulfur, or preferably a reactive ester or ether thereof, with a primary or secondary amine, preferably that of the formula R -NH--R or (b) Dehydrogenating a 2-amino 4 aryl-3,4-dihydro quinoline, more particularly such of the Formula IV (c) Condensing an N-(2-aroyl-phenyl) alkanoic or aralkanoic acid amidine, more particularly such of the Formula V (d) Condensing a Z-amino-fl-aryl-cinnamic acid amide or nitrile, more particularly such of the Formula VI and, if desired, converting any compound obtained into another disclosed compound.

A reactive ester of the 2-hydroxy-4-aryl-quinoline, more particularly is such of a hydrohalic or sulfonic acid, such as hydrochloric, hydrobromic, methane-, ethane-, benzeneor p-toluenesulfonic acid. A corresponding ether is preferably a lower alkyl or aralkyl ether. The dehydrogenation mentioned under item (b) is preferably carried out with catalysts, e.g., palladium catalysts, or oxidation agents, such as potassium ferricyanide. In the reaction according to (a), (c) or (d) any water, alcohol or mercaptan formed may either be distilled off azeotropically or absorbed by a condensing agent, such as a carbodiimid.

The compounds obtained according to said process may be converted into other disclosed compounds by methods in themselves known. Thus, for example, into any primary, secondary or tertiary nitrogen atom, for exampleinto compounds of Formula I in which R stands for hydrogen, a substituent may be introduced, if necessary, after conversion of the compound obtained into a metal, e.g., alkali metal, derivative thereof. This can be done, for example, by reaction with a reactive ester of an appropriate alcohol, for example, that of a hydrohalic or sulfonic acid, e.g., those mentioned above, or by reductive alkylation, i.e., reaction with an appropriate 0X0- compound and subsequent or simultaneous reduction, or with an acid halide or anhydride, whereby acyl derivatives, higher substituted amines or hydrazines, or quaternaries are obtained. In compounds amino-substituted by a-arylalkyl, e.g., benzyl or acyl, e.g., acetyl or phthaloyl radicals, the said radicals can be split off in the usual manner by hydrogenolysis, hydrolysis or hydrazinolysis.

The above-mentioned reactions are carried out according to standard methods, in the presence or absence of diluents, preferably such as are inert to the reagents and are solvents thereof, of catalysts, condensing agents and/ or inert atmospheres, at low temperatures, room temperature or elevated temperatures, at atmospheric or superatmospheric pressure. Condensing agents are especially used in the reaction with said reactive esters in order to eliminate the acid formed. They are basic agents, for example, alkali or alkaline earth metal carbonates or lower alkoxides, or more especially, organic bases such as pyridine or collidine, but particularly aliphatic tertiary amines, such as tri-lower alkylamines, e.g., triethylamine.

The compounds of the invention are obtained in the free form or in the form of their salts, depending on the conditions under which the process is carried out. Salts that are obtained can be converted into the free bases in known manner, for example, with alkalis or ion exchangers. Free bases that are obatined can be converted into salts by reaction with inorganic or organic acids, especially those that are suitable for the formation of therapeutically useful salts. Such acids are, for example, hydrohalic acids, e.g., hydrochloric, hydrobromic, sulfuric, phosphoric, nitric or perchloric acid, aliphatic, alicyclic, araliphatic, aromatic, or heterocyclic carboxylic or sulfonic acids, for example, formic, acetic, propionic, succinic, glycollic, lactic, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic, pyroracemic, phenylacetic, benzoic, 4-aminobenzoic, anthranilic, 4-hydroxybenzoic, salicylic, aminosalicylic, embonic, nicotinic, methanesulfonic, ethanesulfonic, toluenesulfonic, naphthalencsul fonic and sulfanilic acid; methionine, tryptophan, lysine and arginine.

These or other salts, for example, the picrates, can also be used for purification of the bases obtained; the bases are converted into salts, the salts are separated and the bases are liberated from the salts. In view of the close relationship between the free compounds and the compounds in the form of their salts, whenever a free base is referred to in this context, a corresponding salt is also intended, provided such is possible or appropriate under the circumstances.

The invention further includes any variant of the present process, in which an intermediate obtainable at any stage of the process is used as starting material and any remaining steps are carried out, or the process is discontinued at any stage thereof, or in which the start ing materials are formed under the reaction conditions, or in which the reaction components are used in the form of their salts. Mainly, those starting materials should be used in the reaction of the invention that lead to the formation of those compounds indicated above as being specially valuable.

The starting material used in reaction (a) is prepared by condensation of N-alkanoyl or aralkanoyl-Z-aroylanilines or their thioderivatives and, if desired, esterification or etherification of the resulting 2-hydroxyor mercapto-4-aryl-quinoline in the customary manner, for example with the use of phosphorus halogenides or sulfonic acid halides, or reactive esters of alcohols, such as alkyl halogenides or sulfates. The starting material mentioned under item (b) is disclosed in the copending application mentioned above. It can be prepared analogous to reaction (c) from the alcohol corresponding to Formula V or its reactive esters or ethers, or reaction (d) from the saturated acid amide corresponding toFormula VI. The starting material mentioned under item (c) can be prepared from the corresponding alkanoic or aralkanoic acid amide and the 2-aroyl-aniline in the presence of a condensing agent, e.g., phosphorus trichloride. The starting material used in reaction (d) can be prepared by amidation of the corresponding acids, advantageously, their esters or halides.

The starting material mentioned in reaction (a) is new and is considered to be included within the scope of the present invention. Preferably the compounds of Formula III, in which X stands for oxygen and the other symbols have the given meaning, also exhibit valuable pharmacological properties, more particularly diuretic, sodiuretic and also some antiinflammatory effects similar to those of the corresponding Z-amino compounds.

The compounds of the invention can be used, for example, for the manufacture of pharmaceutical compositions containing them in conjunction or admixture with inorganic or organic, solid or liquid pharmaceutical excipients, suitable for enteral, parenteral or topical administration. Suitable excipients are substances that do not react with the compounds of the invention, for example, water, gelatine, sugars, e.g., lactose, glucose or sucrose, starches, e.g., corn starch or arrowroot, stearic acid or salts thereof, e.g., magnesium or calcium stearate, talc, vegetable fats or oils, gums, alginic acid, benzyl alcohols, glycols and other known excipients. The compositions may be, for example, in solid form as tablets, dragees or capsules, or in liquid form as solutions, suspensions or emulsions. They may be sterilized and/or contain adjuvants, such as preserving, stabilizing, Wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and/or buffers. They may further contain other therapeutically valuable substances. Said pharmaceutical compositions are prepared by conventional methods and contain about 0.1 to 75% more particularly 1 to 50%, of the active ingredient. They are also included within the scope of the present invention.

The following examples are intended to illustrate the invention and are not to be construed as being limitations thereon. Temperatures are given in degrees centigrade, and all parts wherever given are parts by weight.

EXAMPLE 1 The mixture of 2.5 g. 2,6-dichloro-4-phenyl-quinoline and 7.5 ml. dimethylamine is heated in a sealed tube to 150 for 6 hours. It is then evaporated, the residue taken up in water, the mixture extracted with chloroform, the extract dried, filtered and evaporated in vacuo. The residue is recrystallized from ethanol to yield the Z-dimethylamino-4-phenyl-6-chloro-quinoline of the formula CsHs more)? melting at -102".

The starting material is prepared as follows: The mixture of 30.0 g. 2-amino-5-chloro-benzophenone, 10.1 g. acetylchloride, 13.0 g. triethylamine and 250 ml. benzene, is refluxed for 1 hour While stirring. After cooling it is filtered, the residue washed with benzene, the filtrate evaporated in vacuo and the residue taken up in water. The mixture is extracted with diethyl ether, the extract washed with diluted hydrochloric acid, dried, filtered and evaporated. The residue is recrystallized from diethyll ether and ethanol to yield the 2-acetylamino-5- chloro-benzophenone melting at 114117.

The mixture of 6.0 g. thereof, 1.0 g. sodium hydroxide, 5 ml. water and 250 ml. ethanol, is refluxed for 30 min utes and then evaporated in vacuo. The residue is taken up in water, the mixture extracted with chloroform, the extract dried, filtered and evaporated. The residue is recrystallized from ethanol to yield the 2-hydroxy-4-phenyl- 6-chloro-quinoline melting at 259-261.

The mixture of 3.2 g. thereof and 25 ml. phosphorus oxychloride is refluxed for 2 hours. After cooling, it is added dropwise to an excess of ice water while stirring. The mixture is extracted with chloroform, the extract dried, filtered and evaporated. The residue is recrystallized from ethanol to yield the 2,6-dichloro-4-phenyl-quinoline, melting at 113l15.

EXAMPLE 2 The mixture of 6.0 g. 2,6-dichloro-3-methyl-4-phenylquinoline and 9.5 ml. dimethylamine is heated in a sealed tube to for 2 days. It is evaporated, the residue taken up in Water, the mixture extracted with diethyl ether, the extract Washed with water, dried, filtered and evaporated. The residue is recrystallized from hexane to yield the 2-dimethylamino-3-methyl-4-phenyl-6-chloroquinoline of the formula our.

melting at 89-91".

The starting material is prepared as follows: The stirred mixture of 50 g. Z-amino--ch1oro-benzophenone, 100 ml. propionic acid anhydride, 0.1 g. sodium acetate and 300 ml. benzene is refluxed for 2 hours. After cooling 100 ml. water is added dropwise while stirring. The organic layer is separated, evaporated, the residue taken up in the solution of 34 g. sodium hydroxide in 50 ml. water and 500 ml. ethanol and the mixture refiuxed for 1 hour while stirring. It is then concentrated, the aqueous concentrate filtered, the residue washed with water and triturated with 400 ml. of 6 N hydrochloric acid for 5 minutes. It is filtered off, washed with water, dissolved in chloroform, the solution treated with charcoal, filtered and evaporated. The residue is triturated with methanol and recrystallized from methanol, to yield the 2-hydroxy-3-methyl-4-phenyl-6-chloro-quinoline melting at 257-260".

The mixture of 5.0 g. thereof and 35 ml. phosphorus oxychloride is refluxed for 2 hours. After cooling, it is added dropwise to an excess of ice water while stirring. The mixture is extracted with chloroform, the extract dried, filtered and evaporated. The residue is recrystallized from methanol to yield the 2,6-dichloro-3-methyl-4- phenyl-quinoline, melting at 182184.

EXAMPLE 3 The mixture of 1.5 g. 2,6-dichloro-3,4-diphenyl-quinoline and 7.5 ml. dimethylamine is heated in a sealed tube to 150 for 6 hours. It is then evaporated, the residue taken up in water, the mixture extracted with chloroform, the extract dried, filtered and evaporated in vacuo. The residue is recrystallized from hexane-benzene, to yield the 2-dimethylamino-3,4-diphenyl-o-chloro-quinoline of the formula Cl- O II melting at 177-179.

The starting material is prepared as follows: To the stirred mixture of 50 g. 2-amino-5-chloro-benzophenone, 300 ml. benzene, 0.1 g. sodium acetate and 22 g. triethylamine, the solution of 88 g. phenylacetyl chloride in 50 ml. benzene is added dropwise. Hereupon the mixture is refluxed for 2 /2 hours and allowed to stand overnight at room temperature. 100 ml. water is added dropwise while stirring, and the mixture again kept overnight. The organic layer is separated and evaporated in vacuo. To the residue the solution of 34 g. sodium hydroxide in 50 ml. water and 500 ml. ethanol is added and the mixture refluxed for 1 hour. It is evaporated, the residue washed with water and triturated with 700 ml. hot aqueous sodium hydroxide and then with 500 ml. 6 N hydrochloric acid. The solid is filtered off, washed with water, dissolved in chloroform, the solution treated with charcoal, filtered and evaporated. The residue is recrystallized from methanol to yield the 2-hydroxy-3,4-diphenyl-6-chloroquinoline melting at 302-305.

The mixture of 14 g. thereof and 100 ml. phosphorus oxychloride is refluxed for 2 hours. After cooling, it is added dropwise to an excess of ice water while stirring. The mixture is extracted with chloroform, the extract dried, filtered and evaporated. The residue is recrystallized from benzene-hexane to yield the 2,6-dichloro-3,4- diphenyl-quinoline melting at 176-177.

EXAMPLE 4 In the manner described in the previous examples, the following compounds of Formula II are prepared from equivalent amounts of the corresponding starting materials of Formula III:

R7+ s R9 R10 R11 H+NH 05H; 4-CH OCcH4 H 218-221 H-l-CH; CuHs 4-CH30-C6H4 H 175-178 H-l-nC H1 H C511 Cl -112 I1+11CgH1 C5115 C0115 Cl 149-151 H-l-CHzCH(CH.-1)2 H CaHs Cl 130-138 11+ 11 CGHB Cl 165-167 rr+Z o1-12 H 0611. or 138-140 H+4-F-C sHr-C Hz C 011 C 5H5 Cl 203-205 H+HOC H2-CH2 H C0115 Cl 146-149 H-i-HO-CHz-CHz C5115 C Cl 170-173 H+HO-CHCH CH3 C0115 Cl 171-174 N H+QCH2 1r C5115 or 115-118 CHM-CH3 11 4-CHsO-C6H4 11 142-145 CH3+CI13 C6115 4-CH30-C5H H 155-158 CHa-l-CHg H CflH5 H 115-119 CH3+CH3 CH CaH5 H 75-79 CH +CHz=CHCHg H CsH CI 66-68 CH3+CH2=C1'ICH2 CH C5115 C1 83-85 C H +CH2=CHCHz CsH C611 Cl 153-155 CHa-l-CaHs-CH CH5 C 115 Cl 150-152 CH +CuH5CH H C H5 Cl -122 CH;+HOCH2-CH2 H CaHs Cl 114-115 CH +HOOH2CH2 CH3 C011 Cl -127 CH3+HOCI'Iz-CH2 CuH5 C5115 Cl 147-150 1,5-pentylene H CeH Cl 128-130 1,5-pentylene CH3 C5H Cl 143-145 1,5-pentylene C611 C6H Cl 240-242 1,6-hexylene H CoH5 Cl 129-131 1,6-hexylene CH CaH 01 92-94 1,6-hexylene C5H CsH5 Cl 185-188 CzH4OC2I'I4 II 00115 Cl 120-122 C zH O-C:H CH C5115 Cl -157 O2H4OC2H4 C51 C5115 01 229-231.

0 3H4N-C 2114 H C 0H5 CI 94-00 1 CzHr-N-CzH4 C11 Cell]; Cl 175-177 C 2H4NC 2114 C 115 05115 01 227-229 CzH4-CH-CzH4 H C511 C1 163165 The starting materials of the formula I Rnfi-Rn X are listed below:

X R9 R10 R11 0 [I C 11 4-CH O-C 11 H 308-311 Cl C611 4-C H OC 01-1 11 -163 0 H C5H5 001 15 II 305-308 C1 CsH5 C 115 H -107 0 H H 4-C IizO-C 6H H 235-237 Cl H 4-C II30C6H4 H 154-158 0 H H 05115 H 259-202 C1 H CsH; II 85-87 0 H CH3 C H H 231-235 C1 CH C0115 H 115-118 EXAMPLE 5 Preparation of 1,000 tablets each containing 50 mg. of the active ingredient.

9 Formula 2-dimethylamino-4-phenyl-6-chloroquinoline 50.0 Colloidal silica 2.5 Corn starch 7.5 Magnesium stearate 1.0 Lactose 89.0 Ethanol (anhydrous), q.s. Purified water, q.s.

Procedure The lactose and the drug substance are passed through a comminuting machine using a screen with 1.2 mm. openings. The stearate, starch and silica, previously mixed with a small portion of the lactose, are added to the sieved powders, which are mixed at low speed for 30 minutes. They are then granulated with ethanol-water 1:1) until suitable granules are formed. The granulate is passed through a comminuting machine (knives forward) using a screen with 4.0 mm. openings. The granulate is dried at 49 to a moisture content below 2%, again passed through a comminuting machine (knives forward) using a screen with 1.4 mm. openings and compressed into 150 mg. tablets using standard concave punches with 7.1 mm. diameter.

In the analogous manner tablets are prepared, each containing 50 mg. of the Z-cyclopropylaminoor 2-piperidino-6-chloro-4-phenyl-quinoline.

EXAMPLE 6 Preparation of 10,000 tablets each containing 50 mg. of the active ingredient.

Formula G. 2 dimethylamino 4 (4 methoxy pheuyl)- quinoline 500.0 Lactose 1,706.0 Corn starch 90.0 Polyethylene glycol 6,000 90.0 Talcum powder 90.0 Magnesium stearate 24.0 Purified water, q.s.

Procedure All the powders are passed through a screen with an opening of 0.6 mm. Then the drug substance, lactose, talcum, magnesium stearate and half of the starch are mixed in a suitable mixer. The other half of the starch is suspended in ml. water and the suspension added to the boiling solution of the polyethylene glycol in 50 ml. water. The paste formed is added to the powders which are granulated, if necessary, with an additional amount of water. The granulate is dried overnight at 35, broken on a screen with 1.2 mm. openings and compressed into tablets using concave punches with 7.1 mm. diameter, uppers bisected.

EXAMPLE 7 The mixture of 1.0 g. 2,6-dichloro-4-phenyl-quinoline and 2.0 g. 4-fluorobenzylamine is heated in a sealed tube to for 4 hours. It is evaporated in vacuo, the residue taken up in diethyl ether, the solution washed with water, dried and filtered. The filtrate is acidified with ethereal hydrochloric acid, the precipitate formed filtered OE and recrystallized from ethanol-methanol to yield the 2-(4- fluoro-benzyl)-4-phenyl-6-chloro-quiuoliue hydrochloride of the formula melting at 274-276.

I claim: 1. A compound of the formula in which R, is phenyl and R is phenyl or mono methoxyphenyl.

References Cited UNITED STATES PATENTS 2,754,293 7/ 1956 Brody 260288 X 3,066,145 11/1962 Sulkowski 260288 3,141,888 7/1964 Loev 260289 3,210,358 10/1965 Pfister et al. 260288 X 3,330,823 7/ 1967 Bernstein et al. 260288 X OTHER REFERENCES Drukker et al.: Chem. Abstr., vol. 65, C01. 20096-8, December 1966.

DONALD G. DAUS, Primary Examiner US. Cl. X.R. 

